Cathepsin B contributes to bile salt-induced apoptosis of rat hepatocytes

L. R. Roberts, H. Kurosawa, S. F. Bronk, P. J. Fesmier, L. B. Agellon, Y. Leung, F. Mao, G. J. Gores

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154 Scopus citations

Abstract

Background and Aims: Bile salt-induced apoptosis is mediated by a trypsin-like nuclear protease. The aims of this study were to identify this protease and to elucidate its mechanistic role in bile salt-induced hepatocyte apoptosis. Methods: Rats, isolated rat hepatocytes, and a rat hepatoma cell line stably transfected with a bile salt transporter (McNtcp.24) were used for this study. Results: In the bile duct-ligated rat, a threefold increase in apoptosis and a fourfold increase in trypsin-like nuclear protease activity were observed. The nuclear protease activity was purified from bile duct-ligated rats and identified as cathepsin B. Specific, structurally dissimilar cathepsin B inhibitors blocked glycochenodeoxycholate (GCDC)-induced apoptosis in cultured rat hepatocytes. Furthermore, stable transfection of McNtcp.24 cells with the complementary DNA for cathepsin B in the antisense orientation reduced cathepsin B activity and GCDC-induced apoptosis by >75%. Next, cathepsin B cellular localization during apoptosis was determined by immunoblot analysis of nuclear cell fractions, immunocytochemistry, and by determining the compartmentation of expressed cathepsin B fused to green fluorescent protein. All three approaches showed translocation of cathepsin B from the cytoplasm to the nucleus during GCDC- induced apoptosis. Conclusions: The data suggest that translocation of cathepsin B from the cytoplasm to the nucleus is a mechanism contributing to bile salt-induced apoptosis of hepatocytes.

Original languageEnglish (US)
Pages (from-to)1714-1726
Number of pages13
JournalGastroenterology
Volume113
Issue number5
DOIs
StatePublished - Jan 1 1997

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Roberts, L. R., Kurosawa, H., Bronk, S. F., Fesmier, P. J., Agellon, L. B., Leung, Y., Mao, F., & Gores, G. J. (1997). Cathepsin B contributes to bile salt-induced apoptosis of rat hepatocytes. Gastroenterology, 113(5), 1714-1726. https://doi.org/10.1053/gast.1997.v113.pm9352877